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Zika virus infection during pregnancy and microcephaly occurrence: a review of literature and Brazilian data

Abstract

In November of 2015, the Ministry of Health of Brazil published an announcement confirming the relationship between Zika virus and the microcephaly outbreak in the Northeast, suggesting that infected pregnant women might have transmitted the virus to their fetuses. The objectives of this study were to conduct a literature review about Zika virus infection and microcephaly, evaluate national and international epidemiological data, as well as the current recommendations for the health teams. Zika virus is an arbovirus, whose main vector is the Aedes sp. The main symptoms of the infection are maculopapular rash, fever, non-purulent conjunctivitis, and arthralgia. Transmission of this pathogen occurs mainly by mosquito bite, but there are also reports via the placenta. Microcephaly is defined as a measure of occipto-frontal circumference being more than two standard deviations below the mean for age and gender. The presence of microcephaly demands evaluation of the patient, in order to diagnose the etiology. Health authorities issued protocols, reports and notes concerning the management of microcephaly caused by Zika virus, but there is still controversy about managing the cases. The Ministry of Health advises notifying any suspected or confirmed cases of children with microcephaly related to the pathogen, which is confirmed by a positive specific laboratory test for the virus. The first choice for imaging exam in children with this malformation is transfontanellar ultrasound. The most effective way to control this outbreak of microcephaly probably caused by this virus is to combat the vector. Since there is still uncertainty about the period of vulnerability of transmission via placenta, the use of repellents is crucial throughout pregnancy. More investigations studying the consequences of this viral infection on the body of newborns and in their development are required.

Keywords
Zika virus; Microcephaly; Aedes mosquitoes; Pregnancy

Introduction

In November of 2015, the Ministry of Health (MOH) of Brazil issued a bulletin confirming the relationship between Zika virus (ZIKV) infection and the microcephaly outbreak in the northeastern region.11 Ministério da Saúde. Ministério da Saúde confirma relação entre virus Zika e microcefalia. Available from: http://portalsaude.saude.gov.br/index.php/cidadao/principal/agencia-saude/21014-ministerio-da-saude-confirma-relacao-entre-virus-zika-e-microcefalia [accessed 16.12.15].
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One of the first records of ZIKV disease in the country is from March of 2015, in the state of Bahia, Northeast Brazil, in which patients with “dengue-like syndrome” showed positivity in blood analysis by molecular biology (real time PCR-RT-PCR).22 Gubio SC, Antonio CB, Silvia IS. Zika virus outbreak, Bahia, Brazil. Emerg Infect Dis. 2015;21:1885–6 [letter]. Autochthonous transmission by ZIKV was confirmed in Brazil in April 201533 Secretaria de Vigilância em Saúde-Ministério da Saúde. Boletim Epidemiológico. Monitoramento dos casos de dengue, febre de Chikungunya e febre pelo vírus Zika até a Semana Epidemiológica 48, 2015. Available from: http://portalsaude.saude.gov.br/images/pdf/2016/janeiro/07/2015-svs-be-pncd-se48.pdf [accessed 16.12.15].
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and in May of the same year, the Brazilian MOH confirmed the circulation of the virus.44 Ministério da saúde. Confirmação do Zika vírus no Brasil. Available from: http://portalsaude.saude.gov.br/index.php/cidadao/principal/agencia-saude/17701-confirmacao-do-zika-virus-no-brasil [accessed 16.12.15].
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From an obstetric perspective, in October of 2015 there was an unusual increase in the number of newborns with microcephaly in the state of Pernambuco (Northeast). Considering that some of the mothers of these babies had a rash during pregnancy55 Secretaria Estadual de Saúde de Pernambuco. Secretaria Executiva de Vigilância em Saúde. Protocolo Clínico e Epidemiológico para investigação de casos de microcefalia no estado de Pernambuco. Versão N° 02. Pernambuco: Secretaria Estadual de Saúde; 2015, 42 pp. the possibility of ZIKV transmission from mother to child, causing neurological defects in the child, was suggested. After conducting tests in a baby born with microcephaly and other malformations in one of the Northeastern states, the presence of the virus in blood and tissues of the patient was detected, proving that assumption.44 Ministério da saúde. Confirmação do Zika vírus no Brasil. Available from: http://portalsaude.saude.gov.br/index.php/cidadao/principal/agencia-saude/17701-confirmacao-do-zika-virus-no-brasil [accessed 16.12.15].
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Currently, due to the progressive extension of cases of microcephaly, corresponding to 4783 suspected and 404 confirmed cases,66 Centro de Operações de Emergências em Saúde Pública sobre Microcefalias. Monitoramento dos casos de microcefalias no Brasil informe epidemiológico N° 11/2016 – semana epidemiológica 04/2016 (24 a 30/01/2016). Available from: http://portalsaude.saude.gov.br/images/pdf/2016/fevereiro/03/COES-Microcefalias---Informe-Epidemiol--gico-11---SE-04-2016---02FEV2016---18h51-VDP.pdf [accessed 05.02.16].
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this situation became extremely concerning to public health, since only 18% of the infected are symptomatic44 Ministério da saúde. Confirmação do Zika vírus no Brasil. Available from: http://portalsaude.saude.gov.br/index.php/cidadao/principal/agencia-saude/17701-confirmacao-do-zika-virus-no-brasil [accessed 16.12.15].
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and there is no treatment for this condition.77 Centers for Disease Control and Prevention. Symptoms. Available from: http://www.cdc.gov/zika/symptoms/index.html [accessed 22.12.15].
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Therefore, the control of pregnant women who might bear a child with microcephaly is impaired, and consequently, a strict monitoring during prenatal care is needed.

In view of this new and alarming scenery, this study aimed to conduct a literature review about ZIKV and microcephaly, evaluate epidemiological data published until February 5th 2016 in national and international levels, as well as to review the current recommendations for the health teams.

Zika virus

The ZIKV is an arbovirus (arthropod-born virus), since part of its reproductive cycle occurs within the body of hematophagous insets. They belong to the Flaviviridae family, and Flavivirus genus, whose members are composed by a protein capsid involved by a lipid envelope, in which the membrane protein and glycoprotein spikes are inserted. The Aedes sp. mosquitoes are the vectors responsible for transmitting this microorganism, as well as Chikungunya virus (CHIKV), dengue virus (DENV), yellow fever virus (YFV), and West Nile fever virus (WNV).88 Musso D, Roche C, Robin E, et al. Potential sexual transmission of Zika virus. Emerg Infect Dis. 2015;21:359–61.

The ZIKV was initially isolated in a Rhesus monkey, at the African Zika forest in Uganda. In the 60s, the first cases of ZIKV infection in humans have been confirmed by serologic evidence in the countries of Uganda, Nigeria, and Senegal.99 Duffy MR, Chen TH, Hancock WT, et al. Zika virus outbreak on Yap Island, Federated States of Micronesia. N Engl J Med. 2009;360:2536–43. The dissemination was so great that in 2007 the first outbreak outside Africa and Asia was reported, on the Yap Island (Federated States of Micronesia). In October of 2013, the largest ZIKV outbreak affected approximately 28,000 inhabitants of the French Polynesia.88 Musso D, Roche C, Robin E, et al. Potential sexual transmission of Zika virus. Emerg Infect Dis. 2015;21:359–61. After two years, in May 2015 the Brazilian MOH issued a statement confirming the first cases identified in the country: 16 people in the Northeast, at Bahia and Rio Grande do Norte states, were tested positive for the virus.44 Ministério da saúde. Confirmação do Zika vírus no Brasil. Available from: http://portalsaude.saude.gov.br/index.php/cidadao/principal/agencia-saude/17701-confirmacao-do-zika-virus-no-brasil [accessed 16.12.15].
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The condition of ZIKV infection is named “dengue-like syndrome” because it resembles an infection caused by the DENV.99 Duffy MR, Chen TH, Hancock WT, et al. Zika virus outbreak on Yap Island, Federated States of Micronesia. N Engl J Med. 2009;360:2536–43. The clinical criteria for diagnosing this self-limited disease are pruritic maculopapular rash plus at least two of the following: fever (generally low grade fever lasting 1–2 days), non-purulent conjunctivitis, polyarthralgia, and periarticular swelling.1010 Protocolo para implantação de unidades sentinelas para Zika vírus. Available from: http://portalsaude.saude.gov.br/images/pdf/2015/dezembro/14/Protocolo-Unidades-Sentinela-Zika-v--rus.pdf [accessed 20.12.15].
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Other signs and symptoms may be present, such as muscle pain, retroocular pain, vomiting, and lymph node hypertrophy.99 Duffy MR, Chen TH, Hancock WT, et al. Zika virus outbreak on Yap Island, Federated States of Micronesia. N Engl J Med. 2009;360:2536–43. Besides, ZIKV infection can affect the central nervous system (CNS). There are reports of a 20-fold increase in the incidence of Guillain–Barre Syndrome (GBS) in Micronesia during the outbreak of ZIKV, in addition to cases of GBS after infection by this pathogen in French Polynesia.1111 Oehler E, Watrin L, Larre P, et al. Zika virus infection complicated by Guillain–Barre syndrome – case report, French Polynesia, December 2013. Euro Surveill. 2014:2014 [rapid communications]. However, about 80% of infections are asymptomatic, what makes the diagnosis and prevention of transmission highly challenging.1212 Lopes N, Nozawa C, Linhares REC. Características gerais e epidemiologia dos arbovírus emergentes no Brasil. Rev Pan-Amaz Saude. 2014;5:55–64.

The detection of viral RNA in the acute phase – up to 10 days from onset of symptoms – by RT-PCR assay is the method of choice for identification of the virus so far. Fortunately, studies to improve the identification of immunoglobulin (IgM) by ELISA are being carried out, but cross-reaction with the DENV is likely to occur in endemic areas of dengue fever.5,5 Secretaria Estadual de Saúde de Pernambuco. Secretaria Executiva de Vigilância em Saúde. Protocolo Clínico e Epidemiológico para investigação de casos de microcefalia no estado de Pernambuco. Versão N° 02. Pernambuco: Secretaria Estadual de Saúde; 2015, 42 pp. 1313 Centers for Disease Control and Prevention. For health care providers: diagnostic testing. Available from: http://www.cdc.gov/zika/hc-providers/index.html [accessed 16.12.15].
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Moreover, another study suggested the possibility of diagnosing the infection from urine samples. Viral RNA was isolated even after 10 days of onset of symptoms, which shows that this technique is suitable for later diagnosis when compared with tests using blood samples.1414 Gourinat AC, O'Connor O, Calvez E, Goarant C, Dupont-Rouzeyrol M. Detection of Zika virus in urine. Emerg Infect Dis. 2015;21:84–6.

Transmission

ZIKV is mainly transmitted by the Aedes aegypti vector, which resides in tropical and subtropical regions, as well as by the Aedes albopictus, inhabitant of the European Mediterranean. After the mosquito's bite, there is an incubation period of about nine days, and then the symptoms ensue.15,15 Musso D, Nhan T, Robin E, et al. Potential for Zika virus transmission through blood transfusion demonstrated during an outbreak in French Polynesia, November 2013 to February 2014. Euro Surveill. 2014;19 [rapid communications]. 1616 Foy BD, Kobylinski KC, Chilson Foy JL, et al. Probable non-vector-borne transmission of Zika virus, Colorado, USA. Emerg Infect Dis. 2011;17:880–2.

Although there is no evidence of sexual transmission in humans by other arboviruses, some authors hypothesized that this could be possible for ZIKV. Patients exposed to endemic areas showed symptoms of the disease and one atypical signal of hematospermia. In such cases, the presence of virus in semen was confirmed by serological tests or by RT-PCR. In addition, one of the sexual partners of these patients had similar symptoms, strengthening this assumption.8,8 Musso D, Roche C, Robin E, et al. Potential sexual transmission of Zika virus. Emerg Infect Dis. 2015;21:359–61. 1616 Foy BD, Kobylinski KC, Chilson Foy JL, et al. Probable non-vector-borne transmission of Zika virus, Colorado, USA. Emerg Infect Dis. 2011;17:880–2.

During the outbreak in French Polynesia, a study to investigate ZIKV in blood donors was carried out using RT-PCR modified technique. It was noted that 3% of donors were asymptomatic hosts of the virus, but no case of infection was identified after blood transfusion. Still, the results suggest that testing for ZIKV must be implemented in the routine of blood donation.15,15 Musso D, Nhan T, Robin E, et al. Potential for Zika virus transmission through blood transfusion demonstrated during an outbreak in French Polynesia, November 2013 to February 2014. Euro Surveill. 2014;19 [rapid communications]. 1717 Vasconcelos PFC. Editorial. Doença pelo vírus Zika: um novo problema emergente nas Américas? Rev Pan-Amaz Saude. 2015;6:9–10.

Regarding perinatal transmission, which is the main focus of this review article, on November 17th 2015 investigators of the Oswaldo Cruz Institute (OCI/Fiocruz) detected the presence of ZIKV genome in amniotic fluid samples of two pregnant women in the state of Paraiba (Northeast), in whom ultrasound exams had confirmed microcephalic fetuses.1818 Fiocruz – Fundação Osvaldo Cruz homepage. IOC/Fiocruz identifica a presença de Zika vírus em dois casos de microcefalia. Available from http://portal.fiocruz.br/pt-br/content/iocfiocruz-identifica-presenca-de-zika-virus-em-dois-casos-de-microcefalia [accessed 09.12.15].
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This fact taken in isolation does not confirm transplacental transmission of the virus but is highly suggestive, since most of the pathogens that cause infections in pregnancy, such as toxoplasmosis, can be detected in the amniotic fluid.1919 Sweet RL, Gibbs RS. Infectious diseases of the female genital tract. 5th ed. Baltimore, MD: Lippincott Willims & Wilkins; 2009. p. 266–300 [perinatal infections].

At the same time, the French Polynesian authorities reported a significant increase in cases of CNS malformations in fetuses born between 2014 and 2015, which was the period of ZIKV outbreak in the region.2020 Pan American Health Organization. World Health Organization. Epidemiological alert. Neurological syndrome, congenital malformations, and Zika virus infection. Implications for public health in the Americas; 2015, December, 11 pp. In this nation, a study2020 Pan American Health Organization. World Health Organization. Epidemiological alert. Neurological syndrome, congenital malformations, and Zika virus infection. Implications for public health in the Americas; 2015, December, 11 pp. suggests that other forms of contagion, such as milk and saliva, ought to be considered. This was evidenced in cases in which RT-PCR was positive for ZIKV in mother's milk, and baby's and mother's saliva, but when inoculated in Vero cells the viruses did not replicate. However, since this kind of transmission can occur in other arboviral diseases, like dengue2121 Barthel A, Gourinat AC, Cazorla C, et al. Breast milk as a possible route of vertical transmission of Dengue virus. Clin Infect Dis. 2013;57:415–7. and West Nile fever,2222 Center for Disease Control and prevention. Possible West Nile virus transmission to an infant through breast-feeding – Michigan, 2002. Morb Mortal Wkly Rep. 2002;51:877–8. these possibilities of contamination should not be neglected.

One of the concerns about the infection in women is the virus latency period, because it is not known if a virus acquired in a non-pregnant woman could have a potential impact on a future fetus. That is why some protocols highlight the importance of also notifying cases in which women have experienced symptoms 40 days before pregnancy.2323 Secretaria Estadual de Saúde do Paraná. Superintendência de vigilância em saúde. Protocolo de vigilância e resposta à ocorrência de microcefalia relacionada à infecção pelo vírus Zika (protocolo complementar ao do ministério da saúde). Versão 1.3. Paraná: Secretaria Estadual de Saúde; 2015, 44 pp.

Microcephaly

Microcephaly is defined as the measurement of head occipto-frontal circumference being more than two standard deviations below the mean for age and gender.2424 Ashwal S, Michelson D, Plawner L, Dobyns WB, Practice Parameter. Evaluation of the child with microcephaly (an evidence – based review). Neurology. 2009;73:887–97. It is known that the brain of microcephalic patients is proportionally smaller, thus about 90% of the cases are associated with some degree of intellectual disability.55 Secretaria Estadual de Saúde de Pernambuco. Secretaria Executiva de Vigilância em Saúde. Protocolo Clínico e Epidemiológico para investigação de casos de microcefalia no estado de Pernambuco. Versão N° 02. Pernambuco: Secretaria Estadual de Saúde; 2015, 42 pp. It is important to remind that microcephaly is not a diagnosis but a clinical finding, therefore further investigation is necessary when facing this situation.2525 Woods CG, Parker A. Investigating microcephaly. Arch Dis Child. 2013;98:707–13.

Regarding the initiation, microcephaly can be classified as primary (congenital) or secondary (postnatal). Primary microcephaly can be detected before 36 weeks of gestation. This may occur by failure or reduction of neurogenesis, by destructive pre-natal insults or by very early degenerative processes.2525 Woods CG, Parker A. Investigating microcephaly. Arch Dis Child. 2013;98:707–13. The secondary microcephaly is caused by any insult factor in the development and function of the CNS. It associates commonly with neurological disorders.2525 Woods CG, Parker A. Investigating microcephaly. Arch Dis Child. 2013;98:707–13.

The etiological approach of microcephaly is extensive, as this can be caused by many genetic, environmental, and maternal factors.55 Secretaria Estadual de Saúde de Pernambuco. Secretaria Executiva de Vigilância em Saúde. Protocolo Clínico e Epidemiológico para investigação de casos de microcefalia no estado de Pernambuco. Versão N° 02. Pernambuco: Secretaria Estadual de Saúde; 2015, 42 pp. Not infrequently, genetic microcephaly progresses with dysmorphic features or concomitantly with other congenital abnormalities and it is very common the association with syndromes, as in Down Syndrome.5,5 Secretaria Estadual de Saúde de Pernambuco. Secretaria Executiva de Vigilância em Saúde. Protocolo Clínico e Epidemiológico para investigação de casos de microcefalia no estado de Pernambuco. Versão N° 02. Pernambuco: Secretaria Estadual de Saúde; 2015, 42 pp. 25,25 Woods CG, Parker A. Investigating microcephaly. Arch Dis Child. 2013;98:707–13. 2626 Abuelo D. Microcephaly syndromes. Semin Pediatr Neurol. 2007;14:118–27. As for environmental and maternal factors, there are hypoxic ischemic insults, placental insufficiency, systemic and metabolic disorders, exposure to teratogens during pregnancy, pregnant women with severe malnutrition, maternal phenylketonuria, and CNS infections (such as rubella, congenital toxoplasmosis, cytomegalovirus infection, herpes, and HIV).5,5 Secretaria Estadual de Saúde de Pernambuco. Secretaria Executiva de Vigilância em Saúde. Protocolo Clínico e Epidemiológico para investigação de casos de microcefalia no estado de Pernambuco. Versão N° 02. Pernambuco: Secretaria Estadual de Saúde; 2015, 42 pp. 2525 Woods CG, Parker A. Investigating microcephaly. Arch Dis Child. 2013;98:707–13. However, in some cases, the etiology of microcephaly cannot be defined (idiopathic).2525 Woods CG, Parker A. Investigating microcephaly. Arch Dis Child. 2013;98:707–13.

Concomitantly with the increase in cases of microcephaly notified by MOH, there was an outbreak of ZIKV infection, which was listed as a possible cause of that malformation.2020 Pan American Health Organization. World Health Organization. Epidemiological alert. Neurological syndrome, congenital malformations, and Zika virus infection. Implications for public health in the Americas; 2015, December, 11 pp. According to information reported by the Brazilian live births information system (SINASC), the extension of the 2015 situation becomes even more significant compared to previous years. From 2010 to 2014 there were around 150 cases reported per year in the country, and currently, suspected cases totaled 4783.6,6 Centro de Operações de Emergências em Saúde Pública sobre Microcefalias. Monitoramento dos casos de microcefalias no Brasil informe epidemiológico N° 11/2016 – semana epidemiológica 04/2016 (24 a 30/01/2016). Available from: http://portalsaude.saude.gov.br/images/pdf/2016/fevereiro/03/COES-Microcefalias---Informe-Epidemiol--gico-11---SE-04-2016---02FEV2016---18h51-VDP.pdf [accessed 05.02.16].
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2727 European Centre for Disease Prevention and Control. Rapid risk assessment: microcephaly in Brazil potentially linked to the Zika virus epidemic – 24 November 2015. Stockholm: ECDC; 2015, 12 pp. Six months have elapsed between the first virus transmission reports (May 2015) and microcephaly outbreak (November 2015), which is the appropriated time for diagnosing cranial abnormalities by prenatal ultrasound examination, suggesting a temporal correlation. The increase in cases of microcephaly occurred in the same area where there had been circulation of virus, indicating also a place correspondence.2727 European Centre for Disease Prevention and Control. Rapid risk assessment: microcephaly in Brazil potentially linked to the Zika virus epidemic – 24 November 2015. Stockholm: ECDC; 2015, 12 pp.

As a result of the increasing impact of this scenery, the MOH deployed the Emergency Operations Center on Health Issues (COES) on November 10th 2015, and after one day, declared “Public Health Emergency of National Importance”.2828 Ministério da Saúde. Ministério da Saúde investiga aumento de casos de microcefalia em Pernambuco. Available from: http://portalsaude.saude.gov.br/index.php/cidadao/principal/agencia-saude/20629-ministerio-da-saudeinvestiga-aumento-de-casos-de-microcefalia-em-pernambuco [accessed 20.12.15].
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The COES weekly publishes epidemiological reports, making it possible to compare and observe a large growth in the number of suspected cases of microcephaly (Fig. 1), and also the progressive involvement of other Brazilian states in different regional areas (Figs. 2 and 3). Of the total of suspected cases, 3670 are under investigation, 404 have been confirmed, and 704 were discarded from surveillance.66 Centro de Operações de Emergências em Saúde Pública sobre Microcefalias. Monitoramento dos casos de microcefalias no Brasil informe epidemiológico N° 11/2016 – semana epidemiológica 04/2016 (24 a 30/01/2016). Available from: http://portalsaude.saude.gov.br/images/pdf/2016/fevereiro/03/COES-Microcefalias---Informe-Epidemiol--gico-11---SE-04-2016---02FEV2016---18h51-VDP.pdf [accessed 05.02.16].
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Fig. 1
Suspected cases of microcephaly. Graph showing the progressive prevalence of suspected cases of microcephaly occurring in Brazil from the beginning of the Zika virus outbreak until January 30, 2016.6,6 Centro de Operações de Emergências em Saúde Pública sobre Microcefalias. Monitoramento dos casos de microcefalias no Brasil informe epidemiológico N° 11/2016 – semana epidemiológica 04/2016 (24 a 30/01/2016). Available from: http://portalsaude.saude.gov.br/images/pdf/2016/fevereiro/03/COES-Microcefalias---Informe-Epidemiol--gico-11---SE-04-2016---02FEV2016---18h51-VDP.pdf [accessed 05.02.16].
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2929 Centro de Operações de Emergências em Saúde Pública sobre Microcefalias. Monitoramento dos casos de microcefalias no Brasil informe epidemiológico N° 01/2015 – semana epidemiológica 46 (15 a 21/11/2015). Available from: http://portalsaude.saude.gov.br/images/pdf/2015/novembro/24/COES-Microcefalias---Informe-Epidemiol--gico---SE-46---24nov2015.pdf [accessed 10.12.15].
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30 Centro de Operações de Emergências em Saúde Pública sobre Microcefalias. Monitoramento dos casos de microcefalias no Brasil informe epidemiológico N° 02/2015 – semana epidemiológica 47 (22 a 28/11/2015). Available from: http://portalsaude.saude.gov.br/images/pdf/2015/novembro/30/coes-microcefalias---informe-epidemiol--gico---se-47.pdf [accessed 10.12.15].
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31 Centro de Operações de Emergências em Saúde Pública sobre Microcefalias. Monitoramento dos casos de microcefalias no Brasil informe epidemiológico N° 03/2015 – semana epidemiológica 48 (29/11/2015 a 05/12/2015). Available from: http://portalsaude.saude.gov.br/images/pdf/2015/dezembro/08/COES-Microcefalias---Informe-Epidemiol--gico---SE-48---08dez2015.pdf [accessed 10.12.15].
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32 Centro de Operações de Emergências em Saúde Pública sobre Microcefalias. Monitoramento dos casos de microcefalias no Brasil informe epidemiológico N° 04/2015 – semana epidemiológica 49 (06 a 12/12/2015). Available from: http://portalsaude.saude.gov.br/images/pdf/2015/dezembro/15/COES-Microcefalias---Informe-Epidemiol--gico---SE-49---15dez2015---10h.pdf [accessed 20.12.15].
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33 Centro de Operações de Emergências em Saúde Pública sobre Microcefalias. Monitoramento dos casos de microcefalias no Brasil informe epidemiológico N° 05/2015 – semana epidemiológica 50 (13 a 19/12/2015). Available from: http://portalsaude.saude.gov.br/images/pdf/2015/dezembro/28/coes-microcefalias-informe-epidemiologico-se50-21dez2015-18h.pdf [accessed 05.02.16].
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34 Centro de Operações de Emergências em Saúde Pública sobre Microcefalias. Monitoramento dos casos de microcefalias no Brasil informe epidemiológico N° 06/2015 – semana epidemiológica 51 (20 a 26/12/2015). Available from: http://portalsaude.saude.gov.br/images/pdf/2015/dezembro/30/COES-Microcefalias---Informe-Epidemiol--gico---SE-51---29dez2015---15h.pdf [accessed 05.02.16].
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35 Centro de Operações de Emergências em Saúde Pública sobre Microcefalias. Monitoramento dos casos de microcefalias no Brasil informe epidemiológico N° 07/2015 – semana epidemiológica 52 (27/12/2015 a 02/01/2016). Available from: http://portalsaude.saude.gov.br/images/pdf/2016/janeiro/05/COES-Microcefalias---Informe-Epidemiol--gico-07---SE-52---04jan2016.pdf [accessed 05.02.16].
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36 Centro de Operações de Emergências em Saúde Pública sobre Microcefalias. Monitoramento dos casos de microcefalias no Brasil informe epidemiológico N° 08/2016 – semana epidemiológica 01/2016 (03 a 09/01/2016). Available from: http://portalsaude.saude.gov.br/images/pdf/2016/janeiro/13/COES-Microcefalias---Informe-Epidemiol--gico-08---SE-01-2016---Valida----o-12jan2016---VALIDADO-PELO-CLAUDIO--e-com-os-estados-por-webconfer--n.pdf [accessed 05.02.16].
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37 Centro de Operações de Emergências em Saúde Pública sobre Microcefalias. Monitoramento dos casos de microcefalias no Brasil informe epidemiológico N° 09/2016 – semana epidemiológica 02/2016 (10 a 16/01/2016). Available from: http://portalsaude.saude.gov.br/images/pdf/2016/janeiro/21/COES-Microcefalias---Informe-Epidemiol--gico-SE-02-2016.pdf [accessed 05.02.16].
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3838 Centro de Operações de Emergências em Saúde Pública sobre Microcefalias. Monitoramento dos casos de microcefalias no Brasil informe epidemiológico N° 10/2016 – semana epidemiológica 03/2016 (17 a 23/01/2016). Available from: http://portalsaude.saude.gov.br/images/pdf/2016/janeiro/28/COES-Microcefalias---Informe-Epidemiol--gico-10---SE-03-2016---26jan2016---20h34.pdf [accessed 05.02.16].
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Fig. 2
Affected federal units. Graph showing the progressive prevalence of suspected cases of microcephaly according to the number of Brazilian states, or Federal units, affected from the beginning of the Zika virus outbreak until January 30, 2016.6,6 Centro de Operações de Emergências em Saúde Pública sobre Microcefalias. Monitoramento dos casos de microcefalias no Brasil informe epidemiológico N° 11/2016 – semana epidemiológica 04/2016 (24 a 30/01/2016). Available from: http://portalsaude.saude.gov.br/images/pdf/2016/fevereiro/03/COES-Microcefalias---Informe-Epidemiol--gico-11---SE-04-2016---02FEV2016---18h51-VDP.pdf [accessed 05.02.16].
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2929 Centro de Operações de Emergências em Saúde Pública sobre Microcefalias. Monitoramento dos casos de microcefalias no Brasil informe epidemiológico N° 01/2015 – semana epidemiológica 46 (15 a 21/11/2015). Available from: http://portalsaude.saude.gov.br/images/pdf/2015/novembro/24/COES-Microcefalias---Informe-Epidemiol--gico---SE-46---24nov2015.pdf [accessed 10.12.15].
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30 Centro de Operações de Emergências em Saúde Pública sobre Microcefalias. Monitoramento dos casos de microcefalias no Brasil informe epidemiológico N° 02/2015 – semana epidemiológica 47 (22 a 28/11/2015). Available from: http://portalsaude.saude.gov.br/images/pdf/2015/novembro/30/coes-microcefalias---informe-epidemiol--gico---se-47.pdf [accessed 10.12.15].
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31 Centro de Operações de Emergências em Saúde Pública sobre Microcefalias. Monitoramento dos casos de microcefalias no Brasil informe epidemiológico N° 03/2015 – semana epidemiológica 48 (29/11/2015 a 05/12/2015). Available from: http://portalsaude.saude.gov.br/images/pdf/2015/dezembro/08/COES-Microcefalias---Informe-Epidemiol--gico---SE-48---08dez2015.pdf [accessed 10.12.15].
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32 Centro de Operações de Emergências em Saúde Pública sobre Microcefalias. Monitoramento dos casos de microcefalias no Brasil informe epidemiológico N° 04/2015 – semana epidemiológica 49 (06 a 12/12/2015). Available from: http://portalsaude.saude.gov.br/images/pdf/2015/dezembro/15/COES-Microcefalias---Informe-Epidemiol--gico---SE-49---15dez2015---10h.pdf [accessed 20.12.15].
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33 Centro de Operações de Emergências em Saúde Pública sobre Microcefalias. Monitoramento dos casos de microcefalias no Brasil informe epidemiológico N° 05/2015 – semana epidemiológica 50 (13 a 19/12/2015). Available from: http://portalsaude.saude.gov.br/images/pdf/2015/dezembro/28/coes-microcefalias-informe-epidemiologico-se50-21dez2015-18h.pdf [accessed 05.02.16].
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34 Centro de Operações de Emergências em Saúde Pública sobre Microcefalias. Monitoramento dos casos de microcefalias no Brasil informe epidemiológico N° 06/2015 – semana epidemiológica 51 (20 a 26/12/2015). Available from: http://portalsaude.saude.gov.br/images/pdf/2015/dezembro/30/COES-Microcefalias---Informe-Epidemiol--gico---SE-51---29dez2015---15h.pdf [accessed 05.02.16].
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35 Centro de Operações de Emergências em Saúde Pública sobre Microcefalias. Monitoramento dos casos de microcefalias no Brasil informe epidemiológico N° 07/2015 – semana epidemiológica 52 (27/12/2015 a 02/01/2016). Available from: http://portalsaude.saude.gov.br/images/pdf/2016/janeiro/05/COES-Microcefalias---Informe-Epidemiol--gico-07---SE-52---04jan2016.pdf [accessed 05.02.16].
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36 Centro de Operações de Emergências em Saúde Pública sobre Microcefalias. Monitoramento dos casos de microcefalias no Brasil informe epidemiológico N° 08/2016 – semana epidemiológica 01/2016 (03 a 09/01/2016). Available from: http://portalsaude.saude.gov.br/images/pdf/2016/janeiro/13/COES-Microcefalias---Informe-Epidemiol--gico-08---SE-01-2016---Valida----o-12jan2016---VALIDADO-PELO-CLAUDIO--e-com-os-estados-por-webconfer--n.pdf [accessed 05.02.16].
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37 Centro de Operações de Emergências em Saúde Pública sobre Microcefalias. Monitoramento dos casos de microcefalias no Brasil informe epidemiológico N° 09/2016 – semana epidemiológica 02/2016 (10 a 16/01/2016). Available from: http://portalsaude.saude.gov.br/images/pdf/2016/janeiro/21/COES-Microcefalias---Informe-Epidemiol--gico-SE-02-2016.pdf [accessed 05.02.16].
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3838 Centro de Operações de Emergências em Saúde Pública sobre Microcefalias. Monitoramento dos casos de microcefalias no Brasil informe epidemiológico N° 10/2016 – semana epidemiológica 03/2016 (17 a 23/01/2016). Available from: http://portalsaude.saude.gov.br/images/pdf/2016/janeiro/28/COES-Microcefalias---Informe-Epidemiol--gico-10---SE-03-2016---26jan2016---20h34.pdf [accessed 05.02.16].
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Fig. 3
Suspected deaths. Graph exhibiting the progressive prevalence of suspected deaths related with microcephaly caused by the ZIKV occurring in Brazil from the beginning of the outbreak until January 30, 2016.6,6 Centro de Operações de Emergências em Saúde Pública sobre Microcefalias. Monitoramento dos casos de microcefalias no Brasil informe epidemiológico N° 11/2016 – semana epidemiológica 04/2016 (24 a 30/01/2016). Available from: http://portalsaude.saude.gov.br/images/pdf/2016/fevereiro/03/COES-Microcefalias---Informe-Epidemiol--gico-11---SE-04-2016---02FEV2016---18h51-VDP.pdf [accessed 05.02.16].
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2929 Centro de Operações de Emergências em Saúde Pública sobre Microcefalias. Monitoramento dos casos de microcefalias no Brasil informe epidemiológico N° 01/2015 – semana epidemiológica 46 (15 a 21/11/2015). Available from: http://portalsaude.saude.gov.br/images/pdf/2015/novembro/24/COES-Microcefalias---Informe-Epidemiol--gico---SE-46---24nov2015.pdf [accessed 10.12.15].
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30 Centro de Operações de Emergências em Saúde Pública sobre Microcefalias. Monitoramento dos casos de microcefalias no Brasil informe epidemiológico N° 02/2015 – semana epidemiológica 47 (22 a 28/11/2015). Available from: http://portalsaude.saude.gov.br/images/pdf/2015/novembro/30/coes-microcefalias---informe-epidemiol--gico---se-47.pdf [accessed 10.12.15].
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31 Centro de Operações de Emergências em Saúde Pública sobre Microcefalias. Monitoramento dos casos de microcefalias no Brasil informe epidemiológico N° 03/2015 – semana epidemiológica 48 (29/11/2015 a 05/12/2015). Available from: http://portalsaude.saude.gov.br/images/pdf/2015/dezembro/08/COES-Microcefalias---Informe-Epidemiol--gico---SE-48---08dez2015.pdf [accessed 10.12.15].
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32 Centro de Operações de Emergências em Saúde Pública sobre Microcefalias. Monitoramento dos casos de microcefalias no Brasil informe epidemiológico N° 04/2015 – semana epidemiológica 49 (06 a 12/12/2015). Available from: http://portalsaude.saude.gov.br/images/pdf/2015/dezembro/15/COES-Microcefalias---Informe-Epidemiol--gico---SE-49---15dez2015---10h.pdf [accessed 20.12.15].
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33 Centro de Operações de Emergências em Saúde Pública sobre Microcefalias. Monitoramento dos casos de microcefalias no Brasil informe epidemiológico N° 05/2015 – semana epidemiológica 50 (13 a 19/12/2015). Available from: http://portalsaude.saude.gov.br/images/pdf/2015/dezembro/28/coes-microcefalias-informe-epidemiologico-se50-21dez2015-18h.pdf [accessed 05.02.16].
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34 Centro de Operações de Emergências em Saúde Pública sobre Microcefalias. Monitoramento dos casos de microcefalias no Brasil informe epidemiológico N° 06/2015 – semana epidemiológica 51 (20 a 26/12/2015). Available from: http://portalsaude.saude.gov.br/images/pdf/2015/dezembro/30/COES-Microcefalias---Informe-Epidemiol--gico---SE-51---29dez2015---15h.pdf [accessed 05.02.16].
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35 Centro de Operações de Emergências em Saúde Pública sobre Microcefalias. Monitoramento dos casos de microcefalias no Brasil informe epidemiológico N° 07/2015 – semana epidemiológica 52 (27/12/2015 a 02/01/2016). Available from: http://portalsaude.saude.gov.br/images/pdf/2016/janeiro/05/COES-Microcefalias---Informe-Epidemiol--gico-07---SE-52---04jan2016.pdf [accessed 05.02.16].
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36 Centro de Operações de Emergências em Saúde Pública sobre Microcefalias. Monitoramento dos casos de microcefalias no Brasil informe epidemiológico N° 08/2016 – semana epidemiológica 01/2016 (03 a 09/01/2016). Available from: http://portalsaude.saude.gov.br/images/pdf/2016/janeiro/13/COES-Microcefalias---Informe-Epidemiol--gico-08---SE-01-2016---Valida----o-12jan2016---VALIDADO-PELO-CLAUDIO--e-com-os-estados-por-webconfer--n.pdf [accessed 05.02.16].
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37 Centro de Operações de Emergências em Saúde Pública sobre Microcefalias. Monitoramento dos casos de microcefalias no Brasil informe epidemiológico N° 09/2016 – semana epidemiológica 02/2016 (10 a 16/01/2016). Available from: http://portalsaude.saude.gov.br/images/pdf/2016/janeiro/21/COES-Microcefalias---Informe-Epidemiol--gico-SE-02-2016.pdf [accessed 05.02.16].
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3838 Centro de Operações de Emergências em Saúde Pública sobre Microcefalias. Monitoramento dos casos de microcefalias no Brasil informe epidemiológico N° 10/2016 – semana epidemiológica 03/2016 (17 a 23/01/2016). Available from: http://portalsaude.saude.gov.br/images/pdf/2016/janeiro/28/COES-Microcefalias---Informe-Epidemiol--gico-10---SE-03-2016---26jan2016---20h34.pdf [accessed 05.02.16].
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Scientific evidence support the relation between ZIKV infection and microcephaly. The literature describes neurotropism as a characteristic of ZIKV in laboratory tests involving rats.3939 Dick GWA. Zika virus (II). Pathogenicity and physical properties. Trans R Soc Trop Med Hyg. 1952;46:521–34. This fact endorses the hypothesis that the virus directly acts on nerve cells of the fetus. Yet, another possibility is that the mechanism occurs through the immune system, such as in Guillain–Barre condition, where antibodies are formed against neuronal myelin sheath.4040 Hughes RAC, Cornblath DR. Guillain–Barré syndrome. Lancet. 2005;366:1653–66.

Different arboviruses have also shown neurological consequences in perinatal infections, such as encephalopathy by CHIKV in humans4141 Gérardin P, Barau G, Michault A, et al. Multidisciplinary prospective study of mother-to-child Chikungunya virus infections on the island of La Réunion. PLoS Med. 2008;5:413–23. and necrotizing encephalopathy and white matter vacuolization by the Akabane virus in sheep and goats.4242 Parsonson IM, Della-Porta AJ, Snowdon WA. Congenital abnormalities in newborn lambs after infection of pregnant sheep with Akabane virus. Infect Immun. 1977;15: 254–62. In addition, arboviruses can cause meningitis, myelitis, neuritis, producing symptoms such as headache, fever, vomiting, peripheral neuropathy, seizures, and even Parkinsonism and chronic epilepsy.4343 Wasay M, Khatri I, Abd-Allah F. Arbovirus infections of the nervous system: current trends and future threats. Neurology. 2015;84:421–3.

Other facts also corroborate this association. In November 2015, the Evandro Chagas Institute declared the presence of ZIKV genome in blood and tissues of a baby with microcephaly, who died 5 min after birth.1,1 Ministério da Saúde. Ministério da Saúde confirma relação entre virus Zika e microcefalia. Available from: http://portalsaude.saude.gov.br/index.php/cidadao/principal/agencia-saude/21014-ministerio-da-saude-confirma-relacao-entre-virus-zika-e-microcefalia [accessed 16.12.15].
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2020 Pan American Health Organization. World Health Organization. Epidemiological alert. Neurological syndrome, congenital malformations, and Zika virus infection. Implications for public health in the Americas; 2015, December, 11 pp. Likewise, according to the epidemiological reports of COES, the number of deaths assumed to be associated with this deformity has expanded significantly since this case. Among the 76 suspected cases, 15 were confirmed.66 Centro de Operações de Emergências em Saúde Pública sobre Microcefalias. Monitoramento dos casos de microcefalias no Brasil informe epidemiológico N° 11/2016 – semana epidemiológica 04/2016 (24 a 30/01/2016). Available from: http://portalsaude.saude.gov.br/images/pdf/2016/fevereiro/03/COES-Microcefalias---Informe-Epidemiol--gico-11---SE-04-2016---02FEV2016---18h51-VDP.pdf [accessed 05.02.16].
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Furthermore, analysis of medical records and interviews with 60 women, who presented a rash during their pregnancy and whose babies were born with microcephaly, showed an absence of other genetic disorders in the family and of findings that might suggest others infections. Thus, the exanthematous disease is probably the putative cause of this deformity.4444 Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Vigilância das Doencas Transmissíveis. Protocolo de vigilância e resposta à ocorrência de microcefalia relacionada à infecção pelo vírus Zika. Brasília: Ministério da Saúde; 2015, 55 pp.

In spite of the relation between microcephaly and ZIKV infection being established in Brazil, some epidemic countries, such as Micronesia and New Calendonia, showed no raise in the number of congenital CNS deformities. It is worth remembering that, however, such sites have considerably smaller population as well as less registered cases, making their limited sample difficult to analyze.2727 European Centre for Disease Prevention and Control. Rapid risk assessment: microcephaly in Brazil potentially linked to the Zika virus epidemic – 24 November 2015. Stockholm: ECDC; 2015, 12 pp.

The microcephaly is an anomaly in which the skull growth is limited due to the lack of stimulation as a result of the deficit in the brain growth.4545 Sadler TW. Embriologia Médica – Langman. 7th ed. Rio de Janeiro: Guanabara Koogan; 1997. p. 250–3 [Chapter 20, Sistema Nervoso Central]. The first trimester of pregnancy is when there is greatest risk that some external factor would cause malformations in the developing child. But when it comes to the CNS, the risk exists throughout pregnancy.55 Secretaria Estadual de Saúde de Pernambuco. Secretaria Executiva de Vigilância em Saúde. Protocolo Clínico e Epidemiológico para investigação de casos de microcefalia no estado de Pernambuco. Versão N° 02. Pernambuco: Secretaria Estadual de Saúde; 2015, 42 pp. According to analyses carried out in Brazil, the risk of microcephaly or congenital abnormalities in newborns associated with ZIKV is greater when the infection occurs in the first trimester of pregnancy.20,20 Pan American Health Organization. World Health Organization. Epidemiological alert. Neurological syndrome, congenital malformations, and Zika virus infection. Implications for public health in the Americas; 2015, December, 11 pp. 2727 European Centre for Disease Prevention and Control. Rapid risk assessment: microcephaly in Brazil potentially linked to the Zika virus epidemic – 24 November 2015. Stockholm: ECDC; 2015, 12 pp. Health authorities of French Polynesia suggested that the critical interval would be during the first or second trimesters.20,20 Pan American Health Organization. World Health Organization. Epidemiological alert. Neurological syndrome, congenital malformations, and Zika virus infection. Implications for public health in the Americas; 2015, December, 11 pp. 2727 European Centre for Disease Prevention and Control. Rapid risk assessment: microcephaly in Brazil potentially linked to the Zika virus epidemic – 24 November 2015. Stockholm: ECDC; 2015, 12 pp. Nevertheless, the gestational period of major vulnerability remains unknown.

Moreover, it has been suggested that microcephaly related to ZIKV could be more aggressive. According to a research with a cohort of 35 babies that were born with microcephaly in Brazilian affected areas, 71% of them had this abnormality in a severe level.4646 Faccini LS, Ribeiro EM, Feitosa IML, et al. Possible association between Zika virus infection and microcephaly — Brazil, 2015. Morb Mortal Wkly Rep. 2016;65:59–62. Consequently, depending on the intensity, it could lead to seizures, hearing and vision impairment, intellectual disability, developmental impairment, and even a life-threatening condition.4747 Centers for Disease Control and Prevention. Facts about microcephaly. Available from: http://www.cdc.gov/ncbddd/birthdefects/microcephaly.html [accessed 05.02.16].
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Detecting, monitoring and managing

Whereas ZIKV infection became a public health emergency, the Brazilian MOH and several state health departments have published protocols, reports and notes concerning the diagnosis and management of congenital microcephaly. As it is a recent condition, there is still much controversy about guidelines and dynamic flowcharts. For this part of the review, we selected technical reports of State Departments of Health (SESA) of two states considered of great importance in this epidemiological situation: São Paulo and Pernambuco, in addition to the MOH protocols.

The MOH published the “Surveillance Protocol in Response to the Occurrence of Microcephaly related to the ZIKV Infection”. This document advises that the presence of exanthema in a pregnant woman, regardless of gestational age, features a suspected case of Zika virus infection, after ruling out other infectious and non-infectious causes. The confirmation is made by a specific positive laboratory test for the pathogen. The MOH recommends two blood samples of the pregnant woman under investigation: the first collected three to five days after the onset of symptoms and the second two to four weeks after the first sample. The material will only be analyzed by PCR if the serology is positive. The ZIKV-specific IgM antibodies can be detected by ELISA or immunofluorescence assays in serum specimens from day five after the onset of symptoms. However, there are no commercial kits for serological diagnosis of ZIKV.44,44 Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Vigilância das Doencas Transmissíveis. Protocolo de vigilância e resposta à ocorrência de microcefalia relacionada à infecção pelo vírus Zika. Brasília: Ministério da Saúde; 2015, 55 pp. 4848 Pan American Health Organization. World Health Organization. Zika virus (ZIKAV) surveillance in the Americas: interim guidance for laboratory detection and diagnosis; 2015, 4 pp.

The management of pregnant women with suspicion of ZIKV infection differs slightly between the SESA of Pernambuco, the SESA of Sao Paulo, and recommendations by the MOH. According to the SESA of Pernambuco, it is necessary to collect a blood sample within five days of the onset of symptoms and a urine sample within eight days, then repeat blood sampling 14–21 days after the start of clinical symptoms. These samples will be analyzed by serology and molecular biology for ZIKV. Still, for this group of pregnant women it is recommended an ultrasound examination between the 32 and 35 weeks of gestation regardless of laboratory test results.55 Secretaria Estadual de Saúde de Pernambuco. Secretaria Executiva de Vigilância em Saúde. Protocolo Clínico e Epidemiológico para investigação de casos de microcefalia no estado de Pernambuco. Versão N° 02. Pernambuco: Secretaria Estadual de Saúde; 2015, 42 pp. For the São Paulo SESA, the only difference from the MOH recommendations is that the second blood drawing should be done 3–4 weeks after the onset of symptoms.4949 Secretaria Estadual de Saúde de São Paulo. Coordenadoria de Controle de Doencas. Centro de Vigilância Epidemiológica. Instituto Adolfo Lutz. Vigilância das microcefalias relacionadas a infecção pelo vírus Zika. Informe Técnico 01. São Paulo: Secretaria Estadual de Saúde; 2015, 12 pp.

For the pregnant women with no history of skin rash and who gave birth to a child with microcephaly, the MOH recommends collecting a mother's blood sample at the time of diagnosis of the child's malformation, and a second blood collection 2–4 weeks after the first sample.4444 Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Vigilância das Doencas Transmissíveis. Protocolo de vigilância e resposta à ocorrência de microcefalia relacionada à infecção pelo vírus Zika. Brasília: Ministério da Saúde; 2015, 55 pp. The report of São Paulo State determines that the second test should be done 3–4 weeks after the first collection,4949 Secretaria Estadual de Saúde de São Paulo. Coordenadoria de Controle de Doencas. Centro de Vigilância Epidemiológica. Instituto Adolfo Lutz. Vigilância das microcefalias relacionadas a infecção pelo vírus Zika. Informe Técnico 01. São Paulo: Secretaria Estadual de Saúde; 2015, 12 pp. while Pernambuco's Protocol does not specify about this lay-off.55 Secretaria Estadual de Saúde de Pernambuco. Secretaria Executiva de Vigilância em Saúde. Protocolo Clínico e Epidemiológico para investigação de casos de microcefalia no estado de Pernambuco. Versão N° 02. Pernambuco: Secretaria Estadual de Saúde; 2015, 42 pp.

The diagnosis of microcephaly can be made during the prenatal and/or postnatal periods. According to the MOH recommendations a case should deemed suspected during pregnancy when the fetus presents head circumference (HC) with two standard deviations below the mean for gestational age or when there is an ultrasound finding with CNS alteration suggestive of congenital infection. Any suspected case of microcephaly caused by ZIKV should be immediately notified to health authorities. In order to confirm, it is necessary to rule out other infectious and non-infectious causes or perform laboratory tests.4444 Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Vigilância das Doencas Transmissíveis. Protocolo de vigilância e resposta à ocorrência de microcefalia relacionada à infecção pelo vírus Zika. Brasília: Ministério da Saúde; 2015, 55 pp. The Pernambuco's Protocol propose that, if there is positivity in these tests, the health professional must issue a notification to the local health authorities, explain the ultrasound findings to the mother, evaluate the need for repeating the ultrasound, keep prenatal care routine – as isolated microcephaly does not characterize pregnancy as high risk – and guide the pregnant woman to psychosocial support by a multidisciplinary team of the health unit.55 Secretaria Estadual de Saúde de Pernambuco. Secretaria Executiva de Vigilância em Saúde. Protocolo Clínico e Epidemiológico para investigação de casos de microcefalia no estado de Pernambuco. Versão N° 02. Pernambuco: Secretaria Estadual de Saúde; 2015, 42 pp. The São Paulo SESA does not specify the correct approach to a case of microcephaly during prenatal care.4949 Secretaria Estadual de Saúde de São Paulo. Coordenadoria de Controle de Doencas. Centro de Vigilância Epidemiológica. Instituto Adolfo Lutz. Vigilância das microcefalias relacionadas a infecção pelo vírus Zika. Informe Técnico 01. São Paulo: Secretaria Estadual de Saúde; 2015, 12 pp.

On the other hand, the postnatal diagnosis used to be determined by the cutoff of HC value lower or equal to 33 cm. But recently the MOH decreased this number to less than or equal to 32 cm, the same value proposed by the WHO, consequently avoiding unnecessary exposure to potentially harmful tests in children with normal skull. When the HC of the newborn is below the third percentile or less than or equal to 32 cm, it is considered a suspected case associated with ZIKV infection, and it is confirmed through positive samples for the virus in the newborn or in the mother during pregnancy. Babies with congenital microcephaly should have samples of blood, umbilical cord, cerebrospinal fluid, and placenta collected at birth and analyzed by ZIKV serology, which, if positive, should be further subjected to molecular biology analysis.4444 Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Vigilância das Doencas Transmissíveis. Protocolo de vigilância e resposta à ocorrência de microcefalia relacionada à infecção pelo vírus Zika. Brasília: Ministério da Saúde; 2015, 55 pp. The preferred imaging exam is transfontanellar ultrasonography (US-TF) in order to avoid exposure to computed tomography scan (CT-scan). For those babies who present early-closing fontanel or if the suspicion persists after diagnostic laboratory and imaging tests, cranial CT-scan without contrast should be performed.5050 Ministério da Saúde. Secretarias Estaduais e Municipais da Saúde. Protocolo de atendimento: mulheres em idade fértil, gestantes, puérperas e bebes com microcefalia. Available from: http://www.corengo.org.br/wp-content/uploads/2015/12/Procolo-de-Atendimento-14_12_2015.pdf [accessed 21.12.15].
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However, the São Paulo SESA recommends the execution of laboratory tests involving merely the umbilical cord, placenta, and cerebrospinal fluid (CSF).4949 Secretaria Estadual de Saúde de São Paulo. Coordenadoria de Controle de Doencas. Centro de Vigilância Epidemiológica. Instituto Adolfo Lutz. Vigilância das microcefalias relacionadas a infecção pelo vírus Zika. Informe Técnico 01. São Paulo: Secretaria Estadual de Saúde; 2015, 12 pp. On the other hand, the Pernambuco SESA advise that only CSF and blood of the fetus and the mother's blood should be tested, and the first imaging evaluation to be done is cranial CT scan without contrast.55 Secretaria Estadual de Saúde de Pernambuco. Secretaria Executiva de Vigilância em Saúde. Protocolo Clínico e Epidemiológico para investigação de casos de microcefalia no estado de Pernambuco. Versão N° 02. Pernambuco: Secretaria Estadual de Saúde; 2015, 42 pp.

As stated, suspected and confirmed cases of microcephaly related to ZIKV infection must be notified. The notification shall be recorded in the online form of Public Health Event Log (RESP-Microcefalias), available on www.resp.saude.gov.br and SINASC online system. This is extremely important for epidemiological understanding of the features of this viral infection, since this data will be stored in a governmental database.4444 Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Vigilância das Doencas Transmissíveis. Protocolo de vigilância e resposta à ocorrência de microcefalia relacionada à infecção pelo vírus Zika. Brasília: Ministério da Saúde; 2015, 55 pp.

The MOH endures the operation of nonspecific laboratory tests for newborns with microcephaly, which are: complete blood count, serum levels of liver aminotransferases, direct and indirect bilirubin, urea, creatinine, and indicators of inflammatory activity, as well as an abdominal ultrasound and echocardiography.4444 Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Vigilância das Doencas Transmissíveis. Protocolo de vigilância e resposta à ocorrência de microcefalia relacionada à infecção pelo vírus Zika. Brasília: Ministério da Saúde; 2015, 55 pp. The Pernambuco SESA also recommends rapid test for syphilis and/or VDRL.55 Secretaria Estadual de Saúde de Pernambuco. Secretaria Executiva de Vigilância em Saúde. Protocolo Clínico e Epidemiológico para investigação de casos de microcefalia no estado de Pernambuco. Versão N° 02. Pernambuco: Secretaria Estadual de Saúde; 2015, 42 pp. The technical report of the State of São Paulo does not specify which laboratory tests must be made in the newborn.4949 Secretaria Estadual de Saúde de São Paulo. Coordenadoria de Controle de Doencas. Centro de Vigilância Epidemiológica. Instituto Adolfo Lutz. Vigilância das microcefalias relacionadas a infecção pelo vírus Zika. Informe Técnico 01. São Paulo: Secretaria Estadual de Saúde; 2015, 12 pp.

Additionally, as microcephaly may be related to neurodevelopmental disorders, the Auditory Evoked Potential testing (BAEP) should be performed as the first choice for hearing assessment, in addition to the Ocular Neonatal Screening Test, for ophthalmic evaluation, and the Biological Newborn Screening Test.5050 Ministério da Saúde. Secretarias Estaduais e Municipais da Saúde. Protocolo de atendimento: mulheres em idade fértil, gestantes, puérperas e bebes com microcefalia. Available from: http://www.corengo.org.br/wp-content/uploads/2015/12/Procolo-de-Atendimento-14_12_2015.pdf [accessed 21.12.15].
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The São Paulo SESA does not specify any of these tests,4949 Secretaria Estadual de Saúde de São Paulo. Coordenadoria de Controle de Doencas. Centro de Vigilância Epidemiológica. Instituto Adolfo Lutz. Vigilância das microcefalias relacionadas a infecção pelo vírus Zika. Informe Técnico 01. São Paulo: Secretaria Estadual de Saúde; 2015, 12 pp. while Pernambuco SESA emphasizes the importance of ophthalmologic examination with fundoscopy in newborns with microcephaly.55 Secretaria Estadual de Saúde de Pernambuco. Secretaria Executiva de Vigilância em Saúde. Protocolo Clínico e Epidemiológico para investigação de casos de microcefalia no estado de Pernambuco. Versão N° 02. Pernambuco: Secretaria Estadual de Saúde; 2015, 42 pp.

A case of stillbirth with microcephaly at any gestational age is deemed suspected if the mother had a history of rash illness during pregnancy. Any suspected cases must be reported, and should undergo confirmation tests for ZIKV identification in the mother or fetal tissue. For this purpose, the MOH recommends collecting samples of 1 cm3 from the child's organs (brain, liver, heart, lung, kidney and spleen) and 3 cm3 from the placenta for molecular and immunohistochemistry biology tests, in addition to the serological evaluation of the mother.4444 Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Vigilância das Doencas Transmissíveis. Protocolo de vigilância e resposta à ocorrência de microcefalia relacionada à infecção pelo vírus Zika. Brasília: Ministério da Saúde; 2015, 55 pp. In regard to this detection, the Pernambuco's Protocol also recommends that baby's tissue samples and placenta should be collected but it does not mention the mother's serum testing,55 Secretaria Estadual de Saúde de Pernambuco. Secretaria Executiva de Vigilância em Saúde. Protocolo Clínico e Epidemiológico para investigação de casos de microcefalia no estado de Pernambuco. Versão N° 02. Pernambuco: Secretaria Estadual de Saúde; 2015, 42 pp. while the São Paulo SESA has no recommendation on stillbirths in its technical report.4949 Secretaria Estadual de Saúde de São Paulo. Coordenadoria de Controle de Doencas. Centro de Vigilância Epidemiológica. Instituto Adolfo Lutz. Vigilância das microcefalias relacionadas a infecção pelo vírus Zika. Informe Técnico 01. São Paulo: Secretaria Estadual de Saúde; 2015, 12 pp.

In case of a positive history for rash during pregnancy followed by an abortion, the MOH considers it as a suspected abortion related to ZIKV infection. It is confirmed only when the pathogen is identified in maternal or fetal tissue. Therefore, it is necessary to collect samples in the same way as for the cases of stillbirths with ZIKV related microcephaly.4444 Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Vigilância das Doencas Transmissíveis. Protocolo de vigilância e resposta à ocorrência de microcefalia relacionada à infecção pelo vírus Zika. Brasília: Ministério da Saúde; 2015, 55 pp. The São Paulo and Pernambuco SESA have not published recommendations for this situation.5,5 Secretaria Estadual de Saúde de Pernambuco. Secretaria Executiva de Vigilância em Saúde. Protocolo Clínico e Epidemiológico para investigação de casos de microcefalia no estado de Pernambuco. Versão N° 02. Pernambuco: Secretaria Estadual de Saúde; 2015, 42 pp. 4949 Secretaria Estadual de Saúde de São Paulo. Coordenadoria de Controle de Doencas. Centro de Vigilância Epidemiológica. Instituto Adolfo Lutz. Vigilância das microcefalias relacionadas a infecção pelo vírus Zika. Informe Técnico 01. São Paulo: Secretaria Estadual de Saúde; 2015, 12 pp.

The most effective plan to combat this outbreak of microcephaly possibly caused by ZIKV is the prevention, fighting the Aedes sp. mosquito by eradicating their breeding grounds.5151 Secretaria Estadual de Saúde do Paraná. Orientação às Equipes de Saúde sobre Microcefalia. Nota Técnica SESA N̊ 01/2015i. Paraná: Secretaria Estadual de Saúde; 2015, 8 pp. It is essential for the community to be oriented on the control of mosquito proliferation in urban and peri-urban areas. For this reason, public health actions, such as home visits by health professionals, advising and guiding the population to eliminate vector sources inside the houses should be implemented. Additionally, using insecticides sprayed by vehicles on public roads and urban sanitation campaigns should be contemplated.44,44 Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Vigilância das Doencas Transmissíveis. Protocolo de vigilância e resposta à ocorrência de microcefalia relacionada à infecção pelo vírus Zika. Brasília: Ministério da Saúde; 2015, 55 pp. 5252 Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Vigilância Epidemiológica. Diretrizes nacionais para prevenção e controle de epidemias de dengue/Ministério da Saúde, Secretaria de Vigilância em Saúde, Departamento de Vigilância Epidemiológica (Série A. Normas e Manuais Técnicos). Brasília: Ministério da Saúde; 2009, 160 pp.

The MOH endorses instructing fertile women, who wish to have a child, about the current situation of microcephaly in the country.5,5 Secretaria Estadual de Saúde de Pernambuco. Secretaria Executiva de Vigilância em Saúde. Protocolo Clínico e Epidemiológico para investigação de casos de microcefalia no estado de Pernambuco. Versão N° 02. Pernambuco: Secretaria Estadual de Saúde; 2015, 42 pp. 5050 Ministério da Saúde. Secretarias Estaduais e Municipais da Saúde. Protocolo de atendimento: mulheres em idade fértil, gestantes, puérperas e bebes com microcefalia. Available from: http://www.corengo.org.br/wp-content/uploads/2015/12/Procolo-de-Atendimento-14_12_2015.pdf [accessed 21.12.15].
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Health authorities do not request to postpone pregnancy, although there is discussion regarding this subject, especially for young couples who could plan for pregnancy after best knowledge and control of this virus. It is important for healthcare professionals to inform the population in general about the disease, belying unofficial information and checking the official data from epidemiological bulletins released weekly (available in www.saude.gov.br/sus). Moreover, it is particularly important to make an early diagnosis of microcephaly and recognize possible brain dysfunctions to guide the patient to a healthcare unit that can implement early brain stimulation measures.5050 Ministério da Saúde. Secretarias Estaduais e Municipais da Saúde. Protocolo de atendimento: mulheres em idade fértil, gestantes, puérperas e bebes com microcefalia. Available from: http://www.corengo.org.br/wp-content/uploads/2015/12/Procolo-de-Atendimento-14_12_2015.pdf [accessed 21.12.15].
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Furthermore, for personal protection, mainly for pregnant women, the MOH suggests using topical repellent products, registered at the National Health Surveillance Agency (ANVISA). It is important to instruct the patients to follow the recommendations on the label and to spray insect repellent on top of the clothing. Researches demonstrate safety of n-diethyl-meta-toluamide (DEET)-based repellents. Nonetheless, other substances are also used in Brazil, such as hydroxyethyl isobutyl piperidine carboxylate (icaridin or picaridin) and ethyl butylacetylaminopropionate (IR3535 or EBAAP), and essential oils such as citronella. Even if these products are safe for regular use, there are no studies in pregnant women. The CDC informs that repellents containing DEET, picaridin, IR3535, some oil of lemon eucalyptus and para-menthane-diol products provide long lasting protection.44,44 Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Vigilância das Doencas Transmissíveis. Protocolo de vigilância e resposta à ocorrência de microcefalia relacionada à infecção pelo vírus Zika. Brasília: Ministério da Saúde; 2015, 55 pp. 5353 Centers for Disease Control and Prevention. Prevention. Available from: http://www.cdc.gov/zika/prevention/index.html [accessed 22.12.15].
http://www.cdc.gov/zika/prevention/index...

Besides repellent topical use, other forms of prevention are also important. It is suggested, whenever possible, the use of long clothes to protect the largest body surface as possible against mosquito's bites. Places and times with the presence of mosquitoes should be avoided, consequently it is important to stay in locations with barriers against the entry of insects, mainly in the period between sunset and dawn, as protective screens, mosquito nets, and air conditioning.44,44 Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Vigilância das Doencas Transmissíveis. Protocolo de vigilância e resposta à ocorrência de microcefalia relacionada à infecção pelo vírus Zika. Brasília: Ministério da Saúde; 2015, 55 pp. 5050 Ministério da Saúde. Secretarias Estaduais e Municipais da Saúde. Protocolo de atendimento: mulheres em idade fértil, gestantes, puérperas e bebes com microcefalia. Available from: http://www.corengo.org.br/wp-content/uploads/2015/12/Procolo-de-Atendimento-14_12_2015.pdf [accessed 21.12.15].
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In case of any alteration in the health condition of pregnant women, especially until the fourth month of pregnancy, it should be reported for the health professional.5151 Secretaria Estadual de Saúde do Paraná. Orientação às Equipes de Saúde sobre Microcefalia. Nota Técnica SESA N̊ 01/2015i. Paraná: Secretaria Estadual de Saúde; 2015, 8 pp. It is important to posit that defects in the CNS may also be caused by other conditions and diseases, such as toxoplasmosis, rubella, abuse of alcohol and illicit drugs during pregnancy, and also genetic syndromes that make differential diagnosis with those conditions associated with ZIKV.55 Secretaria Estadual de Saúde de Pernambuco. Secretaria Executiva de Vigilância em Saúde. Protocolo Clínico e Epidemiológico para investigação de casos de microcefalia no estado de Pernambuco. Versão N° 02. Pernambuco: Secretaria Estadual de Saúde; 2015, 42 pp.

Conclusion

The relation between ZIKV infection during pregnancy and microcephaly in neonates was established by the Brazilian MOH. Therefore, more attention regarding Aedes sp. is required, since it transmits this disease, which has more disastrous consequences than DENV infection. Also, the pregnant woman should be concerned about exposure to endemic areas, and if possible, avoid remaining in such locations. Since there is still no evidence about the period of vulnerability of the embryo's development, the protection by using repellents in an epidemic situation is crucial throughout pregnancy. Notably, it is worth emphasizing that more research is warranted to study viral mechanisms of action on newborns and in their development, because although microcephaly can be easily diagnosed in the delivery room, other possible damage to the fetus can be not so evident.

Conflicts of interest

The authors declare no conflicts of interest.

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Publication Dates

  • Publication in this collection
    May-Jun 2016

History

  • Received
    29 Dec 2015
  • Accepted
    23 Feb 2016
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